WO2007098608A1 - Ligands chiraux, preparation et utilisations au cours de reactions asymetriques - Google Patents
Ligands chiraux, preparation et utilisations au cours de reactions asymetriques Download PDFInfo
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- WO2007098608A1 WO2007098608A1 PCT/CA2007/000348 CA2007000348W WO2007098608A1 WO 2007098608 A1 WO2007098608 A1 WO 2007098608A1 CA 2007000348 W CA2007000348 W CA 2007000348W WO 2007098608 A1 WO2007098608 A1 WO 2007098608A1
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- Prior art keywords
- mmol
- group
- chiral
- ligand
- nmr
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- 239000003446 ligand Substances 0.000 title claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 title description 22
- 238000002360 preparation method Methods 0.000 title description 18
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 12
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 8
- 125000006239 protecting group Chemical group 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 238000011914 asymmetric synthesis Methods 0.000 claims description 4
- IVWWFWFVSWOTLP-YVZVNANGSA-N (3'as,4r,7'as)-2,2,2',2'-tetramethylspiro[1,3-dioxolane-4,6'-4,7a-dihydro-3ah-[1,3]dioxolo[4,5-c]pyran]-7'-one Chemical compound C([C@@H]1OC(O[C@@H]1C1=O)(C)C)O[C@]21COC(C)(C)O2 IVWWFWFVSWOTLP-YVZVNANGSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 abstract description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract description 3
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 39
- -1 2-methyl-3-butyl Chemical group 0.000 description 28
- 239000000047 product Substances 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical compound C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000004296 chiral HPLC Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000000746 allylic group Chemical group 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 229910021645 metal ion Inorganic materials 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- XIDBMAQOPMVFTM-UHFFFAOYSA-N 1-(2-methyl-3,4-dihydro-1h-isoquinolin-1-yl)naphthalen-2-ol Chemical compound C1=CC=C2C(C3C4=CC=CC=C4CCN3C)=C(O)C=CC2=C1 XIDBMAQOPMVFTM-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
- 239000011736 potassium bicarbonate Substances 0.000 description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- COTUWXPUIXXECS-UHFFFAOYSA-N 1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol Chemical compound N1CCC2=CC=CC=C2C1C1=C2C=CC=CC2=CC=C1O COTUWXPUIXXECS-UHFFFAOYSA-N 0.000 description 5
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 150000004780 naphthols Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- VHUBTORJWFMJSR-BLOYMVGPSA-N [1-(6-bromo-2-hydroxynaphthalen-1-yl)-3,4-dihydro-1h-isoquinolin-2-yl] (2s,5r)-5-methyl-2-propan-2-ylcyclohexane-1-carboxylate Chemical compound CC(C)[C@@H]1CC[C@@H](C)CC1C(=O)ON1C(C=2C3=CC=C(Br)C=C3C=CC=2O)C2=CC=CC=C2CC1 VHUBTORJWFMJSR-BLOYMVGPSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- YMJAIEYASUCCMJ-UHFFFAOYSA-N (1-isoquinolin-1-ylnaphthalen-2-yl)-diphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CN=1)C1=CC=CC=C1 YMJAIEYASUCCMJ-UHFFFAOYSA-N 0.000 description 3
- NJMGUEGJMRMONJ-UHFFFAOYSA-N 1-(2-ethyl-3,4-dihydro-1h-isoquinolin-1-yl)naphthalen-2-ol Chemical compound C1=CC=C2C(C3C4=CC=CC=C4CCN3CC)=C(O)C=CC2=C1 NJMGUEGJMRMONJ-UHFFFAOYSA-N 0.000 description 3
- KDPYGLVIHORKLI-UHFFFAOYSA-N 1-(2-propyl-3,4-dihydro-1h-isoquinolin-1-yl)naphthalen-2-ol Chemical compound C1=CC=C2C(C3C4=CC=CC=C4CCN3CCC)=C(O)C=CC2=C1 KDPYGLVIHORKLI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- NKLKRSSMIQQMBL-NTRRVYDUSA-N [1-(2-hydroxynaphthalen-1-yl)-3,4-dihydro-1h-isoquinolin-2-yl] (2s,5r)-5-methyl-2-propan-2-ylcyclohexane-1-carboxylate Chemical compound CC(C)[C@@H]1CC[C@@H](C)CC1C(=O)ON1C(C=2C3=CC=CC=C3C=CC=2O)C2=CC=CC=C2CC1 NKLKRSSMIQQMBL-NTRRVYDUSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- UVJZGFKZGQSKDV-UHFFFAOYSA-N 1,3-diphenylprop-2-enyl acetate Chemical compound C=1C=CC=CC=1C(OC(=O)C)C=CC1=CC=CC=C1 UVJZGFKZGQSKDV-UHFFFAOYSA-N 0.000 description 2
- HDAWKBGPOULHDO-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-1-ol Chemical compound N1CCC2=CC=CC=C2C1C1=C(O)C2=CC=CC=C2C=C1 HDAWKBGPOULHDO-UHFFFAOYSA-N 0.000 description 2
- HLUGRSWHEKPOPM-UHFFFAOYSA-N 2-methyl-1-naphthalen-1-yl-3,4-dihydro-1h-isoquinoline Chemical compound C1=CC=C2C(C3C4=CC=CC=C4CCN3C)=CC=CC2=C1 HLUGRSWHEKPOPM-UHFFFAOYSA-N 0.000 description 2
- NXTDBHPHAVHMCD-UHFFFAOYSA-N 3-iodo-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol Chemical compound N1CCC2=CC=CC=C2C1C1=C2C=CC=CC2=CC(I)=C1O NXTDBHPHAVHMCD-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 2
- 229910006069 SO3H Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229950011260 betanaphthol Drugs 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BMMBLLUHMCQXBQ-UHFFFAOYSA-N (1-isoquinolin-1-ylnaphthalen-2-yl)phosphane Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3P)=NC=CC2=C1 BMMBLLUHMCQXBQ-UHFFFAOYSA-N 0.000 description 1
- KIUPCUCGVCGPPA-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) carbonochloridate Chemical compound CC(C)C1CCC(C)CC1OC(Cl)=O KIUPCUCGVCGPPA-UHFFFAOYSA-N 0.000 description 1
- MJKZGSBXCWNUHV-UHFFFAOYSA-N (6-hydroxynaphthalen-2-yl)-phenylmethanone Chemical compound C1=CC2=CC(O)=CC=C2C=C1C(=O)C1=CC=CC=C1 MJKZGSBXCWNUHV-UHFFFAOYSA-N 0.000 description 1
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- VIVILDBNPAKCMO-UHFFFAOYSA-N 1-(2-benzyl-3,4-dihydro-1h-isoquinolin-1-yl)naphthalen-2-ol Chemical compound OC1=CC=C2C=CC=CC2=C1C(C1=CC=CC=C1CC1)N1CC1=CC=CC=C1 VIVILDBNPAKCMO-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical class COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- ZHVPTERSBUMMHK-UHFFFAOYSA-N 3-aminonaphthalen-2-ol Chemical compound C1=CC=C2C=C(O)C(N)=CC2=C1 ZHVPTERSBUMMHK-UHFFFAOYSA-N 0.000 description 1
- QTLMKLIPXWRFGM-UHFFFAOYSA-N 3-iodo-1-(2-methyl-3,4-dihydro-1h-isoquinolin-1-yl)naphthalen-2-ol Chemical compound C1=CC=C2C(C3C4=CC=CC=C4CCN3C)=C(O)C(I)=CC2=C1 QTLMKLIPXWRFGM-UHFFFAOYSA-N 0.000 description 1
- ORYWNYKNTHPWDG-UHFFFAOYSA-N 3-iodonaphthalen-2-ol Chemical compound C1=CC=C2C=C(I)C(O)=CC2=C1 ORYWNYKNTHPWDG-UHFFFAOYSA-N 0.000 description 1
- ADINSPSNACTQED-UHFFFAOYSA-N 3-methoxy-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol Chemical compound N1CCC2=CC=CC=C2C1C1=C(O)C(OC)=CC2=CC=CC=C21 ADINSPSNACTQED-UHFFFAOYSA-N 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- UDOOJAICWSVTJF-UHFFFAOYSA-N 6-bromo-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol Chemical compound N1CCC2=CC=CC=C2C1C1=C2C=CC(Br)=CC2=CC=C1O UDOOJAICWSVTJF-UHFFFAOYSA-N 0.000 description 1
- NTJFRLVKMVYSQD-UHFFFAOYSA-N 6-methoxy-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol Chemical compound N1CCC2=CC=CC=C2C1C1=C(O)C=CC2=CC(OC)=CC=C21 NTJFRLVKMVYSQD-UHFFFAOYSA-N 0.000 description 1
- POWBOFIOUSLMCI-UHFFFAOYSA-N 7-methoxy-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol Chemical compound N1CCC2=CC=CC=C2C1C1=C(O)C=CC2=CC=C(OC)C=C21 POWBOFIOUSLMCI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YURKMOBHJZKDJU-UHFFFAOYSA-N C(CN1N=[O]c(c2ccccc2cc2)c2[IH]C11)c2c1cccc2 Chemical compound C(CN1N=[O]c(c2ccccc2cc2)c2[IH]C11)c2c1cccc2 YURKMOBHJZKDJU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910018828 PO3H2 Inorganic materials 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- WSCTXQJTZMNPAF-UHFFFAOYSA-N [1-(2-methyl-3,4-dihydro-1h-isoquinolin-1-yl)naphthalen-2-yl] trifluoromethanesulfonate Chemical compound C1=CC=C2C(C3C4=CC=CC=C4CCN3C)=C(OS(=O)(=O)C(F)(F)F)C=CC2=C1 WSCTXQJTZMNPAF-UHFFFAOYSA-N 0.000 description 1
- MUUNMYWWULFZCP-UHFFFAOYSA-N [6-hydroxy-5-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-yl]-phenylmethanone Chemical compound C1=CC2=C(C3C4=CC=CC=C4CCN3)C(O)=CC=C2C=C1C(=O)C1=CC=CC=C1 MUUNMYWWULFZCP-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- XQJHRCVXRAJIDY-UHFFFAOYSA-N aminophosphine Chemical compound PN XQJHRCVXRAJIDY-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- SRXOCFMDUSFFAK-UHFFFAOYSA-N dimethyl peroxide Chemical class COOC SRXOCFMDUSFFAK-UHFFFAOYSA-N 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- COCAUCFPFHUGAA-MGNBDDOMSA-N n-[3-[(1s,7s)-5-amino-4-thia-6-azabicyclo[5.1.0]oct-5-en-7-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(SCC[C@@H]2C3)N)=CC=1NC(=O)C1=CC=C(Cl)C=N1 COCAUCFPFHUGAA-MGNBDDOMSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- MDWRQYBWVTXIIJ-UHFFFAOYSA-N naphthalen-2-yl trifluoromethanesulfonate Chemical compound C1=CC=CC2=CC(OS(=O)(=O)C(F)(F)F)=CC=C21 MDWRQYBWVTXIIJ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000007082 phosphination reaction Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011027 product recovery Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000005055 short column chromatography Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical compound [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present disclosure broadly relates to chiral ligands, their preparation and uses thereof in asymmetric reactions. More specifically, but not exclusively, the present disclosure relates to chiral N, O and N, P ligands, their preparation and use in asymmetric catalysis.
- Asymmetric catalysis takes advantage of chiral catalysts to generate chiral compounds.
- the area of transition metal-catalyzed asymmetric reactions has witnessed the development of numerous novel chiral ligands.
- the chiral ligands BINAP, QUINAP and BINOL have proven to be particularly effective in catalyzing asymmetric reactions (Scheme 1).
- a general feature of these ligands comprises the presence of a single chiral axis.
- Chiral N, P ligands comprise an important type of chirality transfer agent for asymmetric catalysis.
- bidentate ligands comprise the 2- (phosphinoaryl)oxazoline Iigands 4a"c (Scheme 2) and the (phosphinonaphthyl) isoquinoline (QUINAP) ligand. 4d
- the present disclosure relates to chiral ⁇ /, O and N, P ligands.
- the present disclosure relates to chiral ligands represented by a structure of Formula I:
- R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C M 0 alkyl, C 2 - 10 alkenyl, C 2 -10 alkynyl, C 1-10 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(Re) 3 , benzyl and aryl;
- X is selected from the group consisting of OH, OR 7 , O-Prot and P(Ry) 2 ; and [0012] R 6 and R 7 are selected from the group consisting of hydrogen,
- Ci -10 alkyl C 2 -io alkenyl, C 2 -io alkynyl, C 1-10 alkoxy, phenyl, and aryl.
- the present disclosure relates to chiral ligands selected from the group consisting of:
- the present disclosure relates to a racemic mixture of chiral ligands of Formula I.
- the present disclosure relates to a non- racemic mixture of chiral ligands of Formula I.
- the present disclosure relates to chiral ligands of Formula I, selected from the group consisting of L and R enantiomers.
- the present disclosure relates to chiral ligands of Formula I, comprising the L-enantiomer.
- the present disclosure relates to chiral ligands of Formula I, comprising the R-enantiomer. [0019] In an embodiment, the present disclosure relates to a process for preparing chiral ligands represented by a structure of Formula I:
- Ri, R 2 , R 3 , R4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1-1 O alkyl, C 2-1 O alkenyl, C2-10 alkynyl, C 1-10 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(R 6 ) 3 , benzyl and aryl;
- X is selected from the group consisting of OH, OR 7 , O-Prot and P(R 7 ) 2 ;
- R 6 and R 7 are selected from the group consisting of hydrogen,
- Ci-io alkyl C 2-1 O alkenyl, C 3-10 alkenyl, C 1-10 alkoxy, phenyl, and aryl;
- the present disclosure relates to a use of the chiral ligands represented by a structure of Formula I:
- Ri, R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, Ci--I 0 alkyl, C2-10 alkenyl, C 2- io alkynyl, C 1- I 0 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(R 6 ) 3 , benzyl and aryl;
- X is selected from the group consisting of OH, OR 7 , O-Prot and P(R 7 ) 2 ;
- R 6 and R 7 are selected from the group consisting of hydrogen,
- halogen as used herein is understood as referring to fluorine, chlorine, bromine, or iodine.
- halo is understood to encompass fluoro, chloro, bromo, and iodo.
- hydroxy or "hydroxyl,” as used interchangeably herein, represents an -OH group.
- alkyl group as used herein is understood as referring to a saturated, monovalent unbranched or branched hydrocarbon chain.
- alkyl groups include, but are not limited to, C 1-10 alkyl groups.
- Ci -10 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1 -propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1 -propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl-2-pentyl, 2,2-dimethyl-1 -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-1 -butyl, butyl, isobutyl,
- alkenyl as used herein is understood as referring to monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 10 carbons, such as, for example, 2 to 6 carbon atoms or 2 to 4 carbon atoms, containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
- alkynyl as used herein is understood as referring to monovalent straight or branched chain groups of from 2 to 10 carbon atoms comprising one or more carbon-carbon triple bonds and is exemplified by ethynyl, 1-propynyl, and the like.
- alkoxy or "alkyloxy,” as used interchangeably herein, represent an alkyl group attached to the parent molecular group through an oxygen atom.
- exemplary unsubstituted alkoxy groups comprise from 1 to 10 carbons.
- 6- and 7-membered aromatic groups that may include from zero to four heteroatoms in the ring, for example, phenyl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazole, thiazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.
- Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics".
- the aromatic ring can be substituted at one or more ring positions.
- Aryl groups can also be part of a polycyclic group.
- aryl groups include fused aromatic moieties such as naphthyl, anthracenyl, quinolyl, indolyl, and the like.
- protecting group or "prot” as used in the present specification has the meaning usual in synthetic chemistry, particularly for hydroxyl group protection. It refers to any group that may be covalently bound to a hydroxy group, protecting it from undesirable reactions during synthetic procedures. Commonly used hydroxyl-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis, 3 rd Edition” (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Non-limiting suitable protecting groups include f-butyl ethers, benzyl ethers, silyl ethers, MOM (methoxy methyl ethers), MEM (2-methoxy ethoxy methyl ethers) and acetates.
- TFA Trifluoroacetic acid
- TBDPS f-Butyldiphenylsilyl
- AcOH Acetic acid
- TLC Thin Layer Chromatography
- FAB Fast Atom Bombardment.
- Tetrahydroisoquinoline derivatives widely exist in nature and exhibit a wide range of biological and pharmaceutical properties. 6 ' 7
- the present disclosure relates to chiral ligands represented by a structure of Formula I:
- R 1 , R 2 , R3, R4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1- -I 0 alkyl, C 2-1 O alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(Re) 3 , benzyl and aryl;
- X is selected from the group consisting of OH, OR 7 , O-Prot and P(R 7 ) 2 ;
- R 6 and R 7 are selected from the group consisting of hydrogen,
- C 1- - I0 alkyl C 2-10 alkenyl, C 2 -1 0 alkynyl, Ci -10 alkoxy, phenyl, and aryl.
- Non-limiting examples of such chiral ligands are illustrated hereinbelow in Scheme 1.
- 1-Naphthol and derivatives thereof can also be used for the preparation of chiral ligands as contemplated by the present disclosure.
- Yet further naphthol derivatives are known in the art and are within the capacity of a skilled technician.
- the chiral ligands of the present disclosure can be used in the asymmetric synthesis of biological compounds having therapeutic and/or prophylactic properties.
- the chiral ligands of the present disclosure can be used in asymmetric catalysis processes leading to the asymmetric synthesis of biological compounds having therapeutic and/or prophylactic properties.
- the chiral ligands of the present disclosure can be supported onto a chiral auxiliary, polymer, silica gel, ionic liquids, and perfluoroalkyls for supported synthesis, combinatorial synthesis, and for catalyst/product recovery (Scheme 2).
- Scheme 2 the chiral auxiliary, polymer, silica gel, ionic liquids, and perfluoroalkyls
- Table 2 Additional 3,4-dihydroisoquinoline-based ligands.
- the present disclosure relates to the enantioselective preparation of 3,4-dihydroisoquinoline-based ligands Resolution of (1 ,2,3,4-tetrahydro-isoquinolin-1-yl)-naphthale-2-ol (THIQNOL®) using L-tartaric acid in CH 2 CI 2 provided an enantiomeric excess (ee) of about 30%.
- (1 ,2,3,4-tetrahydro-isoquinolin-1 -yl)-naphthale-2-ol can be methylated using CH 3 I to provide the corresponding methylated product in high yield.
- the racemic product is conveniently resolved using L-tartaric acid providing the desired product in excess of 99% ee (Scheme 5).
- the present disclosure relates to chiral amino phosphine ligands.
- Treatment of (-) [1-(2-methyl-1 ,2,3,4-tetrahydro- isoquinolin-1-yl)-naphthale-2-ol] with trifluoromethanesulfonic anhydride in the presence of pyridine yielded the corresponding triflate derivative in 98% yield.
- Subsequent phosphination yielded the desired (S, aR)-3 ⁇ /,P-ligand in 47% yield (Scheme 7).
- the structure and configuration was confirmed by x-ray single crystal analysis.
- the ee of the ligand, relative to the chiral alcohol, was retained by more than 98%, as confirmed by chiral HPLC.
- the present disclosure relates to the use of the chiral ligands in asymmetric synthetic applications.
- Ligand 7a derived from the more polar diastereomer 5a, was used as a chiral catalyst in the reaction between diethylzinc and benzaldehyde. The reaction provided 1-phenylpropan- 1-ol in 46% yield and 60% ee (Scheme 8).
- the present disclosure relates to the use of a chiral ⁇ /,P-ligand in asymmetric synthetic applications.
- Ligand (S, af?)-3 was used as a chiral catalyst in the Pd(O)-catalyzed allylic substitution of racemic 1 ,3-diphenylprop-2-en-1-yl acetate with dimethyl malonate (Table 3).
- Table 3 Asymmetric Pd(0)-catalyzed allylic substitution of racemic 1 ,3-diphenylprop-2-en-1-yl acetate with dimethyl malonate.
- Varian 300 and 400 MHz spectrometers and the chemical shifts were reported in parts per million ( ⁇ ) relative to internal standard TMS (0 ppm) for CDCI 3 .
- the peak patterns are indicated as follows: s, singlet; brs, broad singlet; d, doublet; t, triplet; dt, doublet of triplet; dq, doublet of quartet; dd, doublet of doublet; ddd, doublet of doublet of doublet; dtd, doublet of triplet of doublet; m, multiplet; q, quartet.
- the coupling constants "J" are reported in Hertz (Hz).
- Trifluoromethanesulfonic anhydride (0.7 mL, 4.15 mmol) was slowly added to a solution of (-)-1-(2-methyl-1 ,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1.0 g, 3.46 mmol) and pyridine (0.5 mL, 5.12 mmol) in dry CH 2 CI 2 (20.0 mL) at O 0 C.
- the reaction mixture was stirred over a period of 1 hour and subsequently warmed to room temperature. Following the removal of the solvent under reduced pressure, the residue was submitted to chromatographic separation on silica gel using hexane/EtOAc (10:1 ) as the eluent system.
- the color of the solution gradually changed from blue to dark red.
- the solution was subsequently heated to 11O 0 C under a nitrogen atmosphere over a period of 12 h. Upon cooling to room temperature, the solvent was removed under reduced pressure. The resulting residue was dissolved in CH 2 CI 2 and purified by means of short column chromatography on silica gel, using ethyl acetate as the eluent, followed by column chromatography on silica gel using ethyl acetate/hexane.1 :1 as the eluent system. The desired product was obtained as a colorless solid (472 mg, 47% yield).
- the solid was filtered, suspended in water and treated with an aqueous Na 2 CO 3 solution. After extraction with dichloromethane, the organic phase was dried using MgSO 4 and the solvent was removed under reduced pressure to yield a light purple powder (0.813 g, 2.7 mmol, 44%).
- the mother liquor was evaporated under reduced pressure and the residue subjected to the treatment as described hereinabove.
- the solid was filtered, suspended in water and treated with an aqueous Na2CO3 solution. After extraction with dichloromethane, the organic phase was dried using MgSO 4 and the solvent was removed under reduced pressure to yield a light purple powder (0.117 g , 0.4 mmol, 40%).
- the mother liquor was evaporated under reduced pressure and the residue subjected to the treatment as described hereinabove.
- Enantiopure 1 -(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (0.289 g, 1.0 mmol) was dissolved in THF (3.0 mL) followed by the addition of sodium hydroxide (0.044 g, 1.1 mmol). The pink solution was stirred for 10 minutes, during which time it turned orange in color, lodomethane (68 ⁇ L, 1.1 mmol) was subsequently added and the solution stirred for an additional 20 hours. The mixture was quenched with aqueous NH 4 CI solution and filtered.
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Abstract
L'invention concerne une nouvelle classe de ligands chiraux répondant à la formule (I), dans laquelle : R1, R2, R3, R4 et R5 sont chacun indépendamment un atome d'hydrogène, un halogène, un groupe alkyle en C1 à C10, un alcényle en C2 à C10, un alcynyle en C2 à C10, un alcoxy en C1 à C10, un groupe C(O)R6, un groupe C(O)NHR6, un groupe Si(R6)3, un groupe benzyle ou un groupe aryle ; X est choisi dans le groupe comprenant OH, OR7, O-Prot et P(R7)2, Prot représentant un groupe protecteur ; et R6 et R7 sont chacun un hydrogène, un alkyle en C1 à C10, un alcényle en C2 à C10, un alcynyle en C2 à C10, un alcoxy en C1 à C10, un groupe phényle ou un groupe aryle.
Priority Applications (2)
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CA2643493A CA2643493C (fr) | 2006-03-02 | 2007-03-02 | Derives de naphtol-1-yl-tetrahyroisoquinoline et leur utilisation en tant que ligands chiraux en synthese asymmetrique |
US12/281,267 US8232399B2 (en) | 2006-03-02 | 2007-03-02 | Chiral ligands, their preparation and uses thereof in asymmetric reactions |
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US77809906P | 2006-03-02 | 2006-03-02 | |
US60/778,099 | 2006-03-02 |
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WO2007098608A1 true WO2007098608A1 (fr) | 2007-09-07 |
WO2007098608A8 WO2007098608A8 (fr) | 2007-11-15 |
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PCT/CA2007/000348 WO2007098608A1 (fr) | 2006-03-02 | 2007-03-02 | Ligands chiraux, preparation et utilisations au cours de reactions asymetriques |
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US (1) | US8232399B2 (fr) |
CA (1) | CA2643493C (fr) |
WO (1) | WO2007098608A1 (fr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009073203A1 (fr) * | 2007-12-04 | 2009-06-11 | Amgen Inc. | Ligands du récepteur trp-m8 et leur utilisation dans des traitements |
US8741901B2 (en) | 2004-07-15 | 2014-06-03 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US8802696B2 (en) | 2009-05-12 | 2014-08-12 | Albany Molecular Research, Inc. | 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof |
US8815894B2 (en) | 2009-05-12 | 2014-08-26 | Bristol-Myers Squibb Company | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
WO2015038872A1 (fr) * | 2013-09-13 | 2015-03-19 | The University Of Florida Research Foundation, Inc. | Ligands biaryle |
-
2007
- 2007-03-02 WO PCT/CA2007/000348 patent/WO2007098608A1/fr active Application Filing
- 2007-03-02 US US12/281,267 patent/US8232399B2/en not_active Expired - Fee Related
- 2007-03-02 CA CA2643493A patent/CA2643493C/fr not_active Expired - Fee Related
Non-Patent Citations (7)
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8741901B2 (en) | 2004-07-15 | 2014-06-03 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US9085531B2 (en) | 2004-07-15 | 2015-07-21 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
WO2009073203A1 (fr) * | 2007-12-04 | 2009-06-11 | Amgen Inc. | Ligands du récepteur trp-m8 et leur utilisation dans des traitements |
US8476297B2 (en) | 2007-12-04 | 2013-07-02 | Amgen Inc. | TRP-M8 receptor ligands and their use in treatments |
US8802696B2 (en) | 2009-05-12 | 2014-08-12 | Albany Molecular Research, Inc. | 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof |
US8815894B2 (en) | 2009-05-12 | 2014-08-26 | Bristol-Myers Squibb Company | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
US9173879B2 (en) | 2009-05-12 | 2015-11-03 | Bristol-Myers Squibb Company | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
US9604960B2 (en) | 2009-05-12 | 2017-03-28 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
Also Published As
Publication number | Publication date |
---|---|
US20090306390A1 (en) | 2009-12-10 |
CA2643493A1 (fr) | 2007-09-07 |
CA2643493C (fr) | 2012-07-17 |
US8232399B2 (en) | 2012-07-31 |
WO2007098608A8 (fr) | 2007-11-15 |
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